Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Michael Schaller

Committee Co-Chair

Karen Martin

Committee Member

Elena Pugacheva

Committee Member

Mike Ruppert

Committee Member

Maxim Sokolov

Committee Member

Peter Stoilov

Abstract

The primary cilium is a ubiquitous organelle presented on most human cells. It serves as a crucial signaling hub for multiple pathways including growth factor and G-protein coupled receptors. Loss of primary cilia was observed in various cancers, however, the implications of this event are unclear. Several studies show that loss of cilia promotes cell proliferation, suggesting that alteration of ciliary-dependent signaling can drive the hyperproliferative phenotype of cancer cells, therefore re-establishing primary cilia or targeting altered signaling pathways could be a beneficial strategy as an anti-cancer therapy.;Glioblastoma (GBM) is one of the deadliest cancers with a median survival of 14 months. Such rapid progression of the disease is usually due to the very high growth rate of the tumor and rapid recurrence after surgical resection. Current standard of care for GBM patients includes aggressive radiation and chemotherapy, thus there is a high demand for more targeted approaches. Primary cilia formation is drastically decreased in GBM, however, the role of cilia in glioblastoma proliferation has not been explored. The overall aim of this work was to elucidate the mechanisms of increases in proliferation driven by the loss of cilia, and utilize it to target GBM. The cellular origins of GBM are currently under debate. One of the potential candidates are astrocytes, a highly abundant type of cell in the brain. Loss of primary cilia in human astrocytes stimulates proliferation in the presence of serum. Lysophosphatidic acid (LPA) was found to be a serum component responsible for this phenotype. Lysophosphatidic acid receptor 1 (LPAR1), a G-protein coupled receptor, was found to be accumulated in primary cilium in both astrocytes and GBM cells when cilium was present, while previously reported interactors of LPAR1, Galpha 12 and Galphaq, were excluded from cilium. LPAR1 signaling through Galpha12/Galphaq was previously reported to be responsible for cancer cell proliferation. Such compartmentalization in ciliated cells creates a barrier against unlimited proliferation, which is one of the hallmarks of cancer.;Inhibition of LPA signaling with the small molecule compound Ki16425 in deciliated, highly proliferative astrocytes or GBM cells/xenografts drastically suppresses their growth both in vitro and in vivo. Moreover, Ki16425 brain delivery via PEG-PLGA nanoparticles inhibited tumor progression in an intracranial glioblastoma patient-derived xenograft (PDX) model. Overall, in the current studies, a novel mechanism by which primary cilium restricts proliferation was established. Loss of primary cilia is sufficient to increase mitogenic signaling, and is important for the maintenance of a highly proliferative cancer phenotype. Clinical application of LPA inhibitors may prove beneficial to restrict glioblastoma proliferation and ensure local control of the disease.

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